Lecture 1: Physiology of the cardiovascular system
Contraction and relaxation determine cardiac output.
Excitation-contraction coupling:
Contraction of the heart following electrical stimulation. Happens independent of CNS.
Pacemaker cells in SA node. The AV node is a conduction connection between the ventricles and atria
and slows down the signal between them so they don’t contract at the same time. Fastly distributed
to bundle branches and purkinje fibers.
Calcium determines everything. SR (organelle, extensive membrane structure) is filled with calcium.
Used as amplifying system for muscle cells. Get high calcium in cytosol, you will get a contraction. Ca
entering cell during action potential, but not enough to make entire myocardiocyte contract.
Therefore, use calcium induced calcium release. Ca from action potential comes into membrane >
binds > amplification (1 Ca results in 10 Ca being released) > Ca really high > contraction happens >
SERCA brings Ca back into SR (takes it up as quickly as possible so you get short contractions >
relaxation.
Ca moves away a protein, now actin and myosin can bind.
Pacemaker cells have a rhythm and don’t require input. This happens because of an action potential.
Cells typically more negative charge on the inside. Pacemaker cells change this potential by opening
ion channels. Sodium and calcium are high outside the cell, potassium is always high inside the cell. If
remove the concentration gradient, action potentials cant happen (shot of K for death sentence US).
Slow entry of sodium > reach threshold > calcium channels open > Ca goes in > potential more + >
too + > K channels open > K goes out. All channels voltage gated, which means they respond to
threshold value. Sodium current is responsible for creating automation (is what reaches the
threshold that then opens the Ca channels).
Fight-or-flight response:
HR increases, need more blood in muscles. (Nor)adrenaline is released by sympathetic system.
Acetylcholine is released by parasympathetic system to relax.
Noradrenaline binds to pacemakers cells > kinases activated > phosphorylation of Na channel >
opens bit more > threshold reached faster > HR goes up.
Acetylcholine opens potassium channel bit more > hyperpolarization > takes longer for threshold to
be reached again.
Donor heart
In normal heart, HR is around 100bpm. When receiving donor heart, you cut through para- and
sympathetic NS. Lose control. Normally we are parasympathetically dominant. If you lose this, HR will
be higher (so donor heart has higher heart rate). Takes longer for HR to increase (couple seconds).
Action potential ventricle cells
Do same thing as pacemaker cells, but not the same Na channels. Reacts to cell next to it, doesn’t
just open on its own.
Cardiac cycle:
Filling > isovolumetric contraction > ejection > isovolumetric relaxation > repeat
Blood flow if regulated by changing pressure. It goes to where the pressure is lowest.
,LV pressure is lower than LA, which allows filling of the ventricle. At least 70 mm Hg needed to fill
aorta with blood. To fill ventricle, you need 5 mm Hg. Any damage makes it harder to reach low
pressure (harder to relax).
Passive filling
AV valves open, aorta/pulmonary valve closed. Most filling happens like this
Atrial kick
AV valves open, aorta/pulmonary valve closed. Fills the rest
isovolumetric contraction
AV valves closed, aorta/pulmonary valve closed. Need higher pressure for aortic
valves to open (now around 50mm Hg, need 70)
Ejection
AV valves closed, aorta/pulmonary valve open
isovolumetric relaxation
AV valves closed, aorta/pulmonary valve closed. Relax to go back to low venous
pressure so it can fill up again.
End diastolic volume (EDV) = volume at end of filling phase (max amount of blood in ventricle)
End systolic volume (ESV) = volume that is left in your ventricle (never completely empty)
Stroke volume = end diastolic volume – end systolic volume = 120-40 = 80 ml/slag
Ejection fraction = EDV – ESV / EDV = -67%
HF when <45% (systolic dysfunction).
Difficult to measure volumes with imaging, so ejection fraction used more often in clinic to diagnose
problems (can take it from a 2d image, more practical).
Questions:
Difference between LV and RV
Volumes are equal, but pressure is different. LV has higher pressure than RV, because aorta
needs more pressure than pulmonary artery.
RV much thinner than LV
Cardiac output
CO (ml/min? = stroke volume (SV) x heart rate (HR)
Amount of blood you can pump out each minute.
Athletes have low resting HR, because they changed stroke volume (higher). Need less pumping. All
determined by SA node.
Frank-starling mechanism
Pre-load. Increased filling pressure leads to increased stroke volume. Important for
matching input left and right and at the beginning of an exercise.
Adrenergic stimulation
Heart contracts more and relaxes faster. More force om shorter time.
Afterload
Blood pressure in aorta/pulmonary artery. The pressure needed to open aortic valve.
If have rise in bp > have to contract longer time before the valve opens
Long term adjustments
Hypertrophy of the ventricles (most of the time not a bad thing, but can be risk factor for
HF). E.g. by exercise, pregnancy, hypertension, myocardial infarct. Cardiomyocytes don’t
renew, the existing cells just grow. Makes it vulnerable to damage.
,Lecture 2: Basics of heart failure
Damar Hamlin fell down after hard hit with football > ventricular fibrillation
Complete loss of coordination of the electrical signal. Defibrillate (use AID, give shock) to get
patient back in good rhythm. Patients with high risk of fibrillation can get an ICD (AID but
internally) that shocks them. Defibrillation stops all the cells from contracting and then you
hope they will restart themselves in a good rhythm.
Commotio cordis
See in e.g. baseball. Very rare. When get hard hit in specific part of the cardiac cycle that
stops the heart from contracting like it should.
Stroke volume
The volume of blood you eject. Around 80ml.
Cardiac output
What determines most of your physical fitness. Stroke volume x frequency/heart rate. The
amount of blood you pump per minute. Around 6L per minute normally. During exercise,
both stroke volume and heart rate go up. Can easily have cardiac output of 15L per minute.
Heart rate and life span
Mouse has hr of around 500bpm. Live 2 years. Mammals have around 1 billion heart beats in
a life.
Should you exercise (have high heart rate)? Yes, exercising a lot will make your resting heart
rate go down.
Pressure volume diagram
Describes 1 cardiac cycle (heart beat). See lecture 3 Visch.
Left bottom: end systole, start diastole > increase LV volume and small increase LV pressure >
blood in ventricle in low pressure > pressure goes up bot volume does not go up > ejection
phase lose volume without change in pressure > goes in aorta > isovolumetric relaxation
phase.
Stroke volume is smaller in heart failure patients. EXAMMMMM
Relaxation line (line on bottom, see pp) starts higher and ends higher in hf patients, because
it takes more pressure to fill the heart when it is stiff.
Ejection fraction is the percentage of how much blood you can get out of the heart. Also
smaller in hf patients.
CVD death rates have become much lower (unlike e.g. cancer, of which the mortality has gone up).
Become better at treating certain diseases. Especially mortality after myocardial infarction has gone
down significantly. Treated with PCI (percutaneous coronary intervention). In MI, a coronary artery is
blocked and part of heart muscle doesn’t get blood anymore. PCI opens the artery again (like a
stent). Done in cath lab. Much quicker than coronary bypass.
Previous MI is big risk of developing heart failure later in live.
What is heart failure
Often the end of many cardiac diseases. Its not one thing, it is a syndrome.
After MI there will be damage. Because you can’t regrow heart cells, the rest of the heart
needs to compensate. Can lead to systolic heart failure, a ballooning of the heart. Heart has
lot of volume, but the pump function becomes weak. Reduced stroke volume and ejection
fraction. Vp diagram shifts to right because pressures are more to begin with.
Causes
, Many ways to get hf. Coronary artery diseases, hypertension, valvular diseases,
cardiomyopathies, kidney dysfunction, diabetes and toxin (especially cocaine) abuse.
Symptoms
Fatigue, dyspnea (sob), palpitations (hartkloppingen), angina pectoris (chest pain), increased
risk for arrhythmias.
Dyspnea is caused by LV ventricle not being able to pump blood very well which creates a
“traffic jam” into the lungs. Pressure in LA goes up > increase in pulmonary venous pressure >
pulmonary edema (leakage of fluid into your lungs) > can get fluid in alveoli > sob.
Medication
Diuretics are given for dyspnea (promote kidneys to not reabsorb all the water, increases
urination) which causes loss of blood volume. Nitrates in acute situation. Make heart work
less hard.
Beta blockers counter what adrenaline does (block receptor, reduces work load).
NYHA classification
Used to look at symptom severity.
HF is not only a contraction issue
HFpEF vs HFrEF
HFrEF was just heart failure 20 years ago. Now we know can also have HF without reduced
ejection fraction (HF with preserved EF). More HFpEF patients than HFrEF patients now.
HFrEF: damage to heart > ballooning of heart > reduces systolic function
HFpEF: comorbidity disease. Other things need to go wrong first before getting this. Different
phenotype compared to HFrEF. Have thick wall structure. Stroke volume stays the same as in
normal situation. The filling pressures are increased and have impaired relaxation. Can only
keep stroke volume normal by using very high pressures.
Research
Don’t know what the issue is that causes the thick walls. Important to know before designing
treatment. Can take single cardiomyocyte > stick between 2 needles (dark circles) > measure the
force it takes when the cell is contracting or being pulled on > compare to healthy cell.
Passive stiffness is almost 2x as high in the stiff cells compared to the control.
HFrEF has damage in cardiomyocytes. Endothelial cells don’t play a role.
HFpEF Is not initially caused by cardiomyocyte damage. Endothelial cells dysfunction signal to
cardiomyocytes that make them stiffer.
Therapy
Anti-diabetic drug. Designed to lower blood glucose levels. Reduced mortality quite significantly.
Works independently from the glucose levels in the heart. Seems to cure a lot of things, don’t know
how yet.
Contraction and relaxation determine cardiac output.
Excitation-contraction coupling:
Contraction of the heart following electrical stimulation. Happens independent of CNS.
Pacemaker cells in SA node. The AV node is a conduction connection between the ventricles and atria
and slows down the signal between them so they don’t contract at the same time. Fastly distributed
to bundle branches and purkinje fibers.
Calcium determines everything. SR (organelle, extensive membrane structure) is filled with calcium.
Used as amplifying system for muscle cells. Get high calcium in cytosol, you will get a contraction. Ca
entering cell during action potential, but not enough to make entire myocardiocyte contract.
Therefore, use calcium induced calcium release. Ca from action potential comes into membrane >
binds > amplification (1 Ca results in 10 Ca being released) > Ca really high > contraction happens >
SERCA brings Ca back into SR (takes it up as quickly as possible so you get short contractions >
relaxation.
Ca moves away a protein, now actin and myosin can bind.
Pacemaker cells have a rhythm and don’t require input. This happens because of an action potential.
Cells typically more negative charge on the inside. Pacemaker cells change this potential by opening
ion channels. Sodium and calcium are high outside the cell, potassium is always high inside the cell. If
remove the concentration gradient, action potentials cant happen (shot of K for death sentence US).
Slow entry of sodium > reach threshold > calcium channels open > Ca goes in > potential more + >
too + > K channels open > K goes out. All channels voltage gated, which means they respond to
threshold value. Sodium current is responsible for creating automation (is what reaches the
threshold that then opens the Ca channels).
Fight-or-flight response:
HR increases, need more blood in muscles. (Nor)adrenaline is released by sympathetic system.
Acetylcholine is released by parasympathetic system to relax.
Noradrenaline binds to pacemakers cells > kinases activated > phosphorylation of Na channel >
opens bit more > threshold reached faster > HR goes up.
Acetylcholine opens potassium channel bit more > hyperpolarization > takes longer for threshold to
be reached again.
Donor heart
In normal heart, HR is around 100bpm. When receiving donor heart, you cut through para- and
sympathetic NS. Lose control. Normally we are parasympathetically dominant. If you lose this, HR will
be higher (so donor heart has higher heart rate). Takes longer for HR to increase (couple seconds).
Action potential ventricle cells
Do same thing as pacemaker cells, but not the same Na channels. Reacts to cell next to it, doesn’t
just open on its own.
Cardiac cycle:
Filling > isovolumetric contraction > ejection > isovolumetric relaxation > repeat
Blood flow if regulated by changing pressure. It goes to where the pressure is lowest.
,LV pressure is lower than LA, which allows filling of the ventricle. At least 70 mm Hg needed to fill
aorta with blood. To fill ventricle, you need 5 mm Hg. Any damage makes it harder to reach low
pressure (harder to relax).
Passive filling
AV valves open, aorta/pulmonary valve closed. Most filling happens like this
Atrial kick
AV valves open, aorta/pulmonary valve closed. Fills the rest
isovolumetric contraction
AV valves closed, aorta/pulmonary valve closed. Need higher pressure for aortic
valves to open (now around 50mm Hg, need 70)
Ejection
AV valves closed, aorta/pulmonary valve open
isovolumetric relaxation
AV valves closed, aorta/pulmonary valve closed. Relax to go back to low venous
pressure so it can fill up again.
End diastolic volume (EDV) = volume at end of filling phase (max amount of blood in ventricle)
End systolic volume (ESV) = volume that is left in your ventricle (never completely empty)
Stroke volume = end diastolic volume – end systolic volume = 120-40 = 80 ml/slag
Ejection fraction = EDV – ESV / EDV = -67%
HF when <45% (systolic dysfunction).
Difficult to measure volumes with imaging, so ejection fraction used more often in clinic to diagnose
problems (can take it from a 2d image, more practical).
Questions:
Difference between LV and RV
Volumes are equal, but pressure is different. LV has higher pressure than RV, because aorta
needs more pressure than pulmonary artery.
RV much thinner than LV
Cardiac output
CO (ml/min? = stroke volume (SV) x heart rate (HR)
Amount of blood you can pump out each minute.
Athletes have low resting HR, because they changed stroke volume (higher). Need less pumping. All
determined by SA node.
Frank-starling mechanism
Pre-load. Increased filling pressure leads to increased stroke volume. Important for
matching input left and right and at the beginning of an exercise.
Adrenergic stimulation
Heart contracts more and relaxes faster. More force om shorter time.
Afterload
Blood pressure in aorta/pulmonary artery. The pressure needed to open aortic valve.
If have rise in bp > have to contract longer time before the valve opens
Long term adjustments
Hypertrophy of the ventricles (most of the time not a bad thing, but can be risk factor for
HF). E.g. by exercise, pregnancy, hypertension, myocardial infarct. Cardiomyocytes don’t
renew, the existing cells just grow. Makes it vulnerable to damage.
,Lecture 2: Basics of heart failure
Damar Hamlin fell down after hard hit with football > ventricular fibrillation
Complete loss of coordination of the electrical signal. Defibrillate (use AID, give shock) to get
patient back in good rhythm. Patients with high risk of fibrillation can get an ICD (AID but
internally) that shocks them. Defibrillation stops all the cells from contracting and then you
hope they will restart themselves in a good rhythm.
Commotio cordis
See in e.g. baseball. Very rare. When get hard hit in specific part of the cardiac cycle that
stops the heart from contracting like it should.
Stroke volume
The volume of blood you eject. Around 80ml.
Cardiac output
What determines most of your physical fitness. Stroke volume x frequency/heart rate. The
amount of blood you pump per minute. Around 6L per minute normally. During exercise,
both stroke volume and heart rate go up. Can easily have cardiac output of 15L per minute.
Heart rate and life span
Mouse has hr of around 500bpm. Live 2 years. Mammals have around 1 billion heart beats in
a life.
Should you exercise (have high heart rate)? Yes, exercising a lot will make your resting heart
rate go down.
Pressure volume diagram
Describes 1 cardiac cycle (heart beat). See lecture 3 Visch.
Left bottom: end systole, start diastole > increase LV volume and small increase LV pressure >
blood in ventricle in low pressure > pressure goes up bot volume does not go up > ejection
phase lose volume without change in pressure > goes in aorta > isovolumetric relaxation
phase.
Stroke volume is smaller in heart failure patients. EXAMMMMM
Relaxation line (line on bottom, see pp) starts higher and ends higher in hf patients, because
it takes more pressure to fill the heart when it is stiff.
Ejection fraction is the percentage of how much blood you can get out of the heart. Also
smaller in hf patients.
CVD death rates have become much lower (unlike e.g. cancer, of which the mortality has gone up).
Become better at treating certain diseases. Especially mortality after myocardial infarction has gone
down significantly. Treated with PCI (percutaneous coronary intervention). In MI, a coronary artery is
blocked and part of heart muscle doesn’t get blood anymore. PCI opens the artery again (like a
stent). Done in cath lab. Much quicker than coronary bypass.
Previous MI is big risk of developing heart failure later in live.
What is heart failure
Often the end of many cardiac diseases. Its not one thing, it is a syndrome.
After MI there will be damage. Because you can’t regrow heart cells, the rest of the heart
needs to compensate. Can lead to systolic heart failure, a ballooning of the heart. Heart has
lot of volume, but the pump function becomes weak. Reduced stroke volume and ejection
fraction. Vp diagram shifts to right because pressures are more to begin with.
Causes
, Many ways to get hf. Coronary artery diseases, hypertension, valvular diseases,
cardiomyopathies, kidney dysfunction, diabetes and toxin (especially cocaine) abuse.
Symptoms
Fatigue, dyspnea (sob), palpitations (hartkloppingen), angina pectoris (chest pain), increased
risk for arrhythmias.
Dyspnea is caused by LV ventricle not being able to pump blood very well which creates a
“traffic jam” into the lungs. Pressure in LA goes up > increase in pulmonary venous pressure >
pulmonary edema (leakage of fluid into your lungs) > can get fluid in alveoli > sob.
Medication
Diuretics are given for dyspnea (promote kidneys to not reabsorb all the water, increases
urination) which causes loss of blood volume. Nitrates in acute situation. Make heart work
less hard.
Beta blockers counter what adrenaline does (block receptor, reduces work load).
NYHA classification
Used to look at symptom severity.
HF is not only a contraction issue
HFpEF vs HFrEF
HFrEF was just heart failure 20 years ago. Now we know can also have HF without reduced
ejection fraction (HF with preserved EF). More HFpEF patients than HFrEF patients now.
HFrEF: damage to heart > ballooning of heart > reduces systolic function
HFpEF: comorbidity disease. Other things need to go wrong first before getting this. Different
phenotype compared to HFrEF. Have thick wall structure. Stroke volume stays the same as in
normal situation. The filling pressures are increased and have impaired relaxation. Can only
keep stroke volume normal by using very high pressures.
Research
Don’t know what the issue is that causes the thick walls. Important to know before designing
treatment. Can take single cardiomyocyte > stick between 2 needles (dark circles) > measure the
force it takes when the cell is contracting or being pulled on > compare to healthy cell.
Passive stiffness is almost 2x as high in the stiff cells compared to the control.
HFrEF has damage in cardiomyocytes. Endothelial cells don’t play a role.
HFpEF Is not initially caused by cardiomyocyte damage. Endothelial cells dysfunction signal to
cardiomyocytes that make them stiffer.
Therapy
Anti-diabetic drug. Designed to lower blood glucose levels. Reduced mortality quite significantly.
Works independently from the glucose levels in the heart. Seems to cure a lot of things, don’t know
how yet.
